This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The hypothesis for the study is as follows: Intensive lipid modification with combination therapy will inhibit the progression of atherosclerosis and reduce the incidence of restenosis in femoral arteries following endovascular stenting by decreasing thrombosis and inflammation. In general, we will recruit a total of 120 patients with symptomatic femoral artery occlusive disease in one leg. These patients will be treated with endovascular stenting, and then randomized into two treatment groups: standard of medical care including statin therapy;and standard of medical care with intensive lipid modification using a statin plus ezetimibe and extended release niacin to increase HDL and decrease LDL and TG . Specifically, we will follow these patients for 2 years and study the following specific aims: 1. To determine the effect of intensive lipid modification therapy on progression of atherosclerosis and restenosis of femoral arteries using high resolution MRI image technology to exam both the stented femoral artery for in-stent restenosis and the contralateral fermoral artery for progression of atherosclerosis. 2. To determine the effect of intensive lipid modification therapy on the clinically applicable hemodynamic measurements, clinical symptoms, reduction in systemic major cardiovascular events and the general quality of life of patients following PTA revascularization and stenting by assessment with Duplex ultrasound, segmental limb pressure, segmental pulse volume recording, ankle brachial indicies, treadmill walking distance, absolute claudication and quality of life questionnaires. 3. To determine the effect of intensive lipid modification therapy on lipoproteins, inflammation, and relationship to PAD progression, restenosis, and clinical events. 4. To determine the effect of intensive lipid modification therapy on thrombosis, and relationship to PAD progression, restenosis and clinical events. The association of these blood tests with clinical outcome and femoral artery image will be determined. BACKGROUND AND SIGNIFICANCE It is estimated that peripheral arterial disease (PAD), a manifestation of systemic atherosclerosis, occurs in approximately 12% of the adult population, affecting about 8 million to 10 million persons in the United States &#40;1, 2&#41;. The most common symptomatic manifestation of mild to moderate atherosclerotic PAD is intermittent claudication, which occurs at an annual incidence of 2% in persons over 65 years of age &#40;3&#41;. These patients are at a significantly higher risk of death, compared with healthy controls of a similar age (4). However, despite the high prevalence of PAD and its strong association with cardiovascular morbidity and mortality, the disease receives relatively little attention. These patients are less likely to receive appropriate treatment for their atherosclerotic risk factors than are those with coronary artery disease (5,6). Not only are cardiovascular morbidity and mortality increased in the patient with PAD, but functional status is often severely impaired in those with intermittent claudication. Peak exercise performance in the claudicating patient is about 50% that of age-matched controls, which is equivalent to moderate to severe heart failure using New York Heart Association criteria (7,8). The limited ability to ambulate leads to a disability that is particularly detrimental to quality of life, because both leisure and work activities are often severely curtailed (9). This disability can limit normal activities substantially (9) and because improvement in the absence of an intervention is rare, therapy to relieve intermittent claudication is essential. Several therapeutic techniques currently exist for the treatment of PAD in the lower extremities. Surgical revascularization is a viable alternative because the associated risks of periprocedural mortality and morbidity are low, even at an early stage. In addition, PTA &#40;percutaneous angioplasty&#41;has favorable complication and long-term patency rates and these rates have improved with the advent of endovascular stents. The most common cardiovascular risk factors for CAD and PAD include smoking, diabetes, hypertension, dyslipidemia, and abnormalities of homocysteine metabolism. Treatment of these risk factors may improve cardiovascular outcomes in persons with PAD. Several large clinical trials have determined the benefits of lowering cholesterol concentrations in patients with coronary artery disease (10). In patients with PAD, statin therapy not only lowers serum cholesterol concentrations, but also improves endothelial function, as well as other markers of atherosclerotic risk, such as serum P-selectin concentrations (11,12). A meta-analysis of randomized trials of lipid-lowering therapy in PAD patients revealed a total mortality of 0.7% in the treated patients, as compared with 2.9% in the patients given placebo, a non-significant difference (13). This analysis demonstrated that lipid-lowering therapy reduces disease progression, as measured by angiography, and the severity of claudication. In the Cholesterol Lowering Atherosclerosis Study, lipid-lowering therapy with colestipol plus niacin was associated with stabilization or regression of femoral atherosclerosis (14). The St. Thomas trial, in which 25 men were treated with diet, cholestyramine, nicotinic acid, or clofibrate for an average of 19 months, demonstrated a beneficial effect of therapy on femoral atherosclerosis (15). However, quantitative measurement of atherosclerosis pathology has not been available for evaluating the effect of lipid therapy. Potential application of intensive lipid modification for PAD has not been studied.